Primary Care of the Patient with Cancer

GEORGE F. SMITH; TIMOTHY R. TOONEN

GEORGE F. SMITH, M.D., AND TIMOTHY R. TOONEN, M.D.

Am Fam Physician. 2007;75(8):1207-1214

Author disclosure: Nothing to disclose.

Care of patients with cancer can be enhanced by continued involvement of the primary care physician. The physician's role may include informing the patient of the diagnosis, helping with decisions about treatment, providing psychological support, treating intercurrent disease, continuing patient-appropriate preventive care, and recognizing and managing or comanaging complications of cancer and cancer therapies. Adverse effects of therapy and cancer-related symptoms include nausea, febrile neutropenia, pain, fatigue, depression, and emotional distress. 5-Hydroxytryptamine antagonists are effective in controlling acute nausea associated with chemotherapy. Febrile neutropenia requires systematic evaluation and early empiric antibiotics while awaiting culture results. Cancer-related pain, depression, and fatigue often are underdiagnosed and undertreated. Use of brief screening tools for assessing fatigue and emotional distress can improve management of these symptoms. Exercise prescription, activity management, and psychosocial interventions are useful in treating cancer-related fatigue. The physician must be alert for signs and symptoms of cancer-related emergencies like spinal cord compression, hypercalcemia, tumor lysis syndrome, pericardial tamponade, and superior vena cava syndrome.

More than 1.3 million patients are diagnosed with cancer every year in the United States, and a typical family physician will have three or four patients each year who are given a new diagnosis of cancer.¹ These patients and their families face not only a life-threatening disease but a flurry of subspecialty consultations, medical tests, and treatments that may be difficult and disruptive. During the course of the patient's cancer care, the family physician can remain an important resource for the patient and family, providing an empathetic and credible source of information, support, and advice as well as medical treatment for intercurrent illness, preoperative evaluation, postoperative care, and coordination of subspecialty care (Table 1²).

Clinical recommendation	Evidence rating	References
Treat chemotherapy-related nausea and vomiting with 5-hydroxytryptamine antagonists.	A	¹⁴
Manage chemotherapy-related anemia with epoetin alfa.	A	²⁷, ²⁸
Recommend exercise to mitigate fatigue and improve functional status in patients undergoing chemotherapy and radiation therapy.	B	³⁸, ³⁹
Treat cancer-related fatigue with psychosocial intervention.	B	⁴⁰
Megestrol (Megace) improves weight gain and appetite in patients with cachexia caused by cancer.	A	⁵², ⁵³
Massage and aromatherapy massage may enhance psychological well-being, including relief of anxiety, in patients with cancer.	B	⁶¹

Be a case manager

Maintain regular contact

Be available

Have knowledge of community resources and covered services

Address ongoing health maintenance needs

Provide appropriate pain management

Assess for pathologic depression and other psychiatric pathology

Be aware of therapeutic options

Communicate with and support the patient

Patients followed by an oncologist alone are less likely to receive preventive care, and care for noncancer chronic illness that is consistent with guidelines, than patients followed jointly by an oncologist and a primary care physician.³ For patients with advanced disease, primary care continuity may reduce emergency department visits and make it more likely that the patient will be able to die at home.^4,5

The responsibility to inform a patient about a cancer diagnosis may fall on the family physician. The SPIKES mnemonic, which was developed to guide this process, is provided in Table 2.⁶ If cues indicate, touch may be beneficial in conveying concern and empathy, and the presence of significant others should be encouraged.⁷ Most patients want full information about the extent of the disease, treatment options, adverse effects, symptoms, and prognosis, but want some control over the timing, mode, and extent of information they receive.^8,9 Regardless of the prognosis, some hope can and should be conveyed.

S = Setting up the interview	Arrange for some privacy; sit down; manage time constraints and interruptions; involve significant others; make a connection with the patient
P = Perception	Before you tell, ask what patient knows
I = Invitation	Explore the patient's wishes for receiving information
K =Knowledge and information given to the patient	Warn the patient that bad news is coming
E = Addressing the patient's Emotions with Empathetic responses	Continue empathetic statements and gestures until patient is calm
S = Strategy and Summary	Discuss treatment options if patient is ready; a clear plan for the future will reduce anxiety; confirm the patient's understanding of the discussion

Adverse Effects of Chemotherapy and Radiation

Although chemotherapy and radiation treatments are usually directed by a subspecialist, the family physician must be aware of potential adverse effects and, in some practice settings, may be called on to manage them.

NAUSEA AND VOMITING

Approximately 70 to 80 percent of patients treated with chemotherapy experience nausea and vomiting,¹⁰ which may be acute (occurring within a few hours after chemotherapy), delayed (occurring 24 or more hours after chemotherapy), breakthrough or refractory (occurring despite prophylactic treatment), or anticipatory (occurring before chemotherapy treatment). The emetogenic potential of chemotherapeutic agents varies from mild to severe.¹¹ Drug dose, schedule and route of administration, and patient variability also are factors.

Antiemetic therapy is most effective if given before chemotherapy and maintained while the emetic potential of the agent continues. Oral formulations are as effective as parenteral or rectal routes if the patient is able to swallow and digest tablets. Lorazepam (Ativan), metoclopramide (Reglan), and prochlorperazine (Compazine) often are used for moderate- to low-emetic-risk chemotherapy and for breakthrough nausea.

The introduction of 5-hydroxytryptamine (5-HT) receptor antagonists in the early 1990s represented a significant advance in antiemetic therapy.¹² Currently, 5-HT antagonists are most widely used in practice with high- to moderate-risk chemotherapy and include ondansetron (Zofran), granisetron (Kytril), dolasetron (Anzemet), and palonosetron (Aloxi). Trials with these agents indicate that they are highly effective in controlling acute nausea and vomiting associated with chemotherapy and have minimal adverse effects.^12–14 They are equally effective for acute nausea,¹⁵ but palonosetron, which has a much higher affinity for the 5-HT receptor and a longer half-life than the other 5-HT antagonists, is more effective than dolasetron in preventing delayed emesis.¹⁶ The coadministration of dexamethasone improves the effectiveness of 5-HT antagonists in controlling acute emesis. However, one study found that adding a 5-HT antagonist to dexamethasone for the treatment of delayed nausea and vomiting did not result in an improved anti-emetic effect over dexamethasone alone.¹⁷ Aprepitant (Emend) augments the activity of 5-HT antagonists and dexamethasone to inhibit acute and delayed emesis induced by cisplatin (Platinol).^18,19

Nausea and vomiting also can occur secondary to radiation treatment and are most likely in patients undergoing whole body or upper abdominal radiation. Higher total dose of radiation, larger amount of tissue radiated, and higher daily fraction of radiation are also factors in the severity of nausea and vomiting.²⁰

FEVER AND NEUTROPENIA

Fever in a patient undergoing chemotherapy is common and worrisome. In the guidelines developed by the Infectious Diseases Society of America²¹ (IDSA), fever is defined as a single oral temperature higher than 100.9° F (38.3° C) or an oral temperature of 100.4° F (38.0° C) or higher for more than one hour.

An absolute neutrophil count less than 500 per mm³ (0.5 × 10⁹ per L) is defined as severe neutropenia. The severity of infection is inversely related to the neutrophil count, with the greatest risk of bacteremia at absolute neutrophil levels lower than 100 per mm³ (0.1 × 10⁹ per L).²² Evaluation of the patient with neutropenia includes physical examination (with attention to indwelling vascular access devices), laboratory data, radiographs, and blood and urine cultures.

After initial evaluation, patients may be risk stratified (Table 3^21,23) to determine if they are candidates for outpatient treatment or if hospital admission is required. In either case, empiric broad-spectrum antibiotics should be started. Delayed treatment may result in increased mortality.^21,24 No single antibiotic or antibiotic combination can be uniformly recommended for all febrile neutropenic patients. Initial therapy is selected after considering the most likely potential infecting organism, site of infection, organ function (e.g., kidney, liver), medication allergies, and recent antibiotic treatment.

High risk*

Inpatient status

Serum creatinine greater than 2 mg per dL (180 μmol per L), LFT greater than three times the normal limit

Uncontrolled or progressive cancer

Pneumonia

Significant comorbid illness

Prolonged severe neutropenia

ANC less than 100 per mm³ (0.1 × 10⁹ per L)

ANC less than 500 per mm³ (0.5 × 10⁹ per L) for more than seven days

Low risk†

Outpatient status

No comorbid illness

Short duration of neutropenia

Creatinine less than 2 mg per dL, LFT of three times the normal limit or less

Good functional status, active and independent

The most widely used outpatient antibiotic choice is an oral fluoroquinolone or amoxicillin/clavulanate (Augmentin). Commonly used empiric intravenous antibiotic monotherapies include carbapenems (e.g., imipenem/cilastatin [Primaxin], meropenem [Merrem]), and extended-spectrum antipseudomonal cephalosporins (e.g., ceftazidime [Fortaz], cefepime [Maxipime]). Dual therapy agents include an aminoglycoside with antipseudomonal penicillin (with or without a betalactamase inhibitor) or an extended-spectrum anti-pseudomonal cephalosporin; and ciprofloxacin (Cipro) with antipseudomonal penicillin. Outpatients should be treated for 10 to 14 days. Inpatients should be treated three to four days pending sensitivity, then continue with oral medication as an outpatient for 10 to 14 days.^21,24

According to IDSA and National Comprehensive Cancer Network guidelines, diagnostic reassessment should occur if fever does not improve in three to four days. Although most patients with cancer-related febrile neutropenia will recover without major complications, involvement of a subspecialist should be considered when the patient's fever does not improve after three or four days of appropriate antimicrobial treatment or when the patient has septic shock, methicillin-resistant Staphylococcus aureus infection, or signs and symptoms of invasive fungal infection.

Other Adverse Effects and Cancer-Related Emergencies

Other common adverse effects and their treatments are listed in Tables 4^25–28 and 5.^29,30 There is strong evidence that epoetin alfa (Epogen) reduces transfusion requirement and improves quality of life in cancer patients with anemia.^27,28 The maximal incremental benefit occurs between hemoglobin levels of 11 and 12 g per dL (110 to 120 g per L).³¹ The family physician must be alert to signs and symptoms indicating a cancer-related emergency (Table 6).³²

Adverse effect	Onset	Evaluation	Treatment
Diarrhea	Seven to 10 days after start of chemotherapy	Stool bacterial culture	If Clostridium difficile positive, use metronidazole (Flagyl) If C. difficile negative, use an antimotility agent such as loperamide (Imodium) or diphenoxylate/atropine (Lomotil)
		Stool C. difficile antigen
		Fecal occult blood testing
Alopecia	Seven to 10 days after start of chemotherapy	—	Shave remaining hair from head; wear wigs or scarves
Chemotherapy-induced anemia	Several weeks after start of chemotherapy	Rule out other causes of anemia (e.g., bleeding, hemolysis, nutritional deficiency)	Recombinant erythropoietin (epoetin alfa [Epogen], darbepoetin alfa [Aranesp]) if hemoglobin is less than 11 g per dL (110 g per L)

Site of radiation	Adverse effect	Treatment
Oral cavity	Mucositis	Saline/bicarbonate lavage; viscous lidocaine (Xylocaine), diphenhydramine elixir (Benadryl), simethicone (Mylanta), or Gelclair (oral gel that forms a protective coating that provides durable pain relief); sucralfate (Carafate) oral suspension
Oral cavity	Thrush	Antifungal treatments (nystatin [Mycostatin] swish and swallow, fluconazole [Diflucan] or itraconazole [Sporanox] orally)
Salivary glands	Xerostomia	Sialogogues (e.g., pilocarpine [Salagen]); intravenous amifostine (Ethyol) infusion daily before radiation therapy
Mandible	Temporomandibular joint fibrosis	Stretching exercises
Mandible	Osteoradionecrosis	Complete dental work before starting radiation therapy; hyperbaric oxygen; pentoxifylline (Trental)
Lungs	Pneumonitis	Prednisone (30 to 60 mg daily for 2 to 3 weeks) with appropriate tapering
Lungs	Fibrosis	Supportive care (e.g., oxygen, bronchodilators); pentoxifylline
Prostate	Obstructive uropathy	Alpha blockers (e.g., terazosin [Hytrin], doxazosin [Cardura], tamsulosin [Flomax]); finasteride (Propecia)
Bowel	Diarrhea	Low-residue diet; loperamide (Imodium); diphenoxylate/atropine (Lomotil); cholestyramine (Questran); octreotide (Sandostatin)
Bowel	Proctitis	Hydrocortisone cream; glucocorticoid retention enemas; mesalamine suppositories (Rowasa); sulfasalazine (Azulfidine)

Condition	Cause	Signs/symptoms	Diagnostic tests	Treatment
Spinal cord compression	Spinal column metastasis, local spread intramedullary metastasis	Back pain (early); neurologic deficit of the legs (late)	Magnetic resonance imaging of the spine	Corticosteroids, radiation, surgery, treat underlying malignancy
Superior vena cava syndrome	Mediastinal tumors, venous catheters	Neck, facial, periocular swelling; dyspnea; cough; head pressure; hoarseness; nasal congestion; syncope	Computed tomography	Corticosteroids, radiation, supportive care, treat underlying malignancy
Pericardial tamponade	Lymphatic obstruction, pericardial metastasis	Dyspnea; orthopnea; chest pain; weakness	Echocardiography, pericardiocentesis	Pericardiocentesis, sclerosis, chemotherapy, pericardial window or stripping
Hypercalcemia	Bone metastasis, parathyroid hormone–related protein production, calcitriol excretion	Confusion; lethargy; sleepiness	Laboratory tests for calcium and electrolytes	Intravenous hydration, bisphosphonates
Tumor lysis syndrome	Rapid tumor cell destruction from chemotherapy, multiple electrolyte abnormalities, hyperuricemia	Nausea, weakness, myalgia, dark urine, arrhythmias	Laboratory tests for electrolytes and uric acid	Prevent by hydration, allopurinol (Zyloprim); treat electrolyte abnormalities, acidosis

Ongoing Care After Chemotherapy or Radiation

Following initial treatment, patients with persistent cancer may have multiple symptoms including pain, fatigue, weakness, anorexia, dry mouth, constipation, early satiety, dyspnea, weight loss, and insomnia; these may occur regardless of the histologic type of cancer.³³ The most significant of these are fatigue, pain, and the symptoms associated with depression. According to a National Institutes of Health consensus statement, too few cancer patients receive adequate treatment for these symptoms.³⁴

FATIGUE

Fatigue is the most prevalent symptom in cancer patients, occurring in almost all patients undergoing aggressive treatments including radiation, chemotherapy, and bone marrow transplantation.^35,36 Fatigue may begin early in the course of treatment and persist for many months or years after treatment. Unlike simple tiredness or situational fatigue, it is more debilitating and severe; less likely to be relieved by simple rest; and may lead to withdrawal from meaningful and enjoyable activities. Among employed patients with cancer-related fatigue, 75 percent changed their employment status and 28 percent discontinued work entirely as a result of fatigue.³⁷

Seven clinical factors have been identified as causative elements in fatigue: pain, emotional distress, sleep disturbance, anemia, nutrition, activity level, and other comorbidities.³⁸ These factors must be addressed in mitigating cancer-related fatigue. Patients with moderate or severe fatigue need further evaluation and intervention.³⁸

It has been shown that exercise, including walking and aerobic and resistance training, have beneficial effects on some symptoms related to cancer, including fatigue, distress, anxiety, and depressive symptoms.³⁸ A recent systematic review indicates a trend toward improved physical functioning with exercise programs.³⁹ An exercise prescription should take into account the patient's history and any physical constraints that may impact exercise safety and compliance.

There also is strong evidence that psychosocial interventions, including support groups, stress management, education, and behavioral intervention, are effective in treating fatigue in patients with cancer.⁴⁰

PAIN

Thirty to 50 percent of patients undergoing active treatment, and about 70 to 90 percent of those with advanced solid tumors, experience chronic pain.⁴¹ Appropriate treatment of pain can result in 90 percent of cancer patients achieving adequate relief.⁴¹ Barriers to pain control include lack of physician knowledge of adequate treatment of pain, unrealistic concerns about narcotic addiction, patient underreporting of symptoms, and lack of emphasis on symptom control in comparison with disease management.⁴¹ Uncontrolled severe pain is an emergency and requires aggressive treatment.

MENTAL HEALTH

Studies have shown an increased prevalence of depression in cancer patients.^42,43 The amount of other psychiatric and psychological problems in cancer patients is not different from the general population and is less than in psychiatric patients.⁴²

Depression may adversely affect the course of malignant disease. Depression has been linked to a reduced chance of survival in breast cancer patients.^44,45 Older women with depression before cancer diagnosis were more likely to receive nondefinitive treatment for cancer.⁴⁵ Depression in cancer patients is underdiagnosed and undertreated for a number of reasons.⁴⁶ Physicians may accept affective symptoms as normal and may underestimate the severity of depressive symptoms.⁴⁷ Although studies have been limited, the existing data support the use of antidepressant medication to treat depression in cancer patients.^48,49

The concept of psychosocial distress in cancer patients is useful, emphasizing the continuum of unpleasant emotional experiences ranging from normal feelings of fear, sadness, vulnerability, and spiritual crisis to more traditional clinical issues (e.g., anxiety, panic, clinical depression). This approach recognizes the considerable overlap of common “normal” distress reactions in cancer patients with pathologic reactions while encouraging intervention before symptoms rise to the level of a clinical syndrome.⁵⁰ Assessment of distress can be accomplished with an interview or a short questionnaire given periodically and at times of increased vulnerability (Figure 1).⁵⁰

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NUTRITION

Maintaining adequate nutrient intake during active treatment can be challenging for cancer patients. Nausea, anorexia, and changes in taste and smell contribute to poor nutrition. Smaller, more frequent meals and nutrient-dense liquid supplements may improve nutrient intake. Supplementation with large amounts of vitamins and minerals during cancer treatment theoretically could reduce effectiveness of chemotherapy or radiation therapy by enhancing repair of cellular oxidative damage to cancer cells. The American Cancer Society recommends limiting intake of antioxidant vitamins to tolerable upper limits of Institute of Medicine Dietary Reference Intakes during chemotherapy or radiotherapy.⁵¹ Particular attention should be paid to food safety when cancer patients may be immunosuppressed.⁵¹

CACHEXIA

Despite attempts to maintain adequate nutrition, cachexia occurs in up to 80 percent of patients with advanced cancer. Characterized by loss of fat and muscle mass, this wasting does not halt or correct with nutritional supplementation. To date, no highly effective therapy has been found. Megestrol (Megace) may improve appetite, calorie intake, sense of well-being, and weight gain in cancer patients, but taking it does not result in increased muscle mass or improvement in performance status. The optimal dose has not been defined.^52,53 Corticosteroids may improve appetite and the feeling of well-being; however, the effect is short-lived. Dexamethasone, having the least mineralocorticoid effect, is preferred, and a single morning dose may prevent associated insomnia.⁵⁴ A recent randomized, placebo-controlled study in patients with advanced pancreatic cancer showed attenuation of loss of weight and muscle mass with use of the tumor necrosis factor α–synthesis inhibitor thalidomide (Thalomid), but further confirmatory studies are needed before it can be recommended.⁵⁵ Studies investigating use of fish oil or omega-3 fatty acid supplementation to treat cachexia have had mixed results.^56–58

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Most cancer patients use one or more modalities of complementary or alternative medicine (e.g., massage, aromatherapy, prayer, acupuncture, imagery, hypnosis, biofeedback, meditation, journaling, music therapy, therapeutic touch, vitamins, herbs).^59,60 Although evidence of effectiveness is lacking for many of these modalities, a Cochrane review of randomized controlled trials determined that massage and aromatherapy massage conferred short-term benefits on psychological well-being, particularly with anxiety reduction, in patients with cancer.⁶¹

Although the risks of alternative therapies are generally low, avoiding or abandoning effective conventional treatment may be a significant risk. Herbal remedies may have an adverse effect on chemotherapy, particularly through effects on the cytochrome P450 isozymes and the intestinal drug transport proteins.⁶²

The Family Context

Despite the obvious stress on the patient's spouse or partner, a diagnosis of cancer is not associated with a decline in the quality of the marriage relationship.⁶³ Although patients with cancer, in particular women with breast cancer, may fear abandonment by their spouse, most marriages remain stable.⁶⁴ A significant minority of couples coping with breast cancer report they have grown closer as a result of the diagnosis.⁶⁵

Children of patients with cancer experience fear, mood disturbance, feelings of guilt, and distress.⁶⁶ Adolescent daughters are especially at risk of psychosomatic symptoms and mood disturbances.

As cancer progresses and the burden of care increases, the caregiver's psychological morbidity can equal or exceed that of the patient.⁶⁷ Family physicians are in an ideal position to understand the impact of a cancer diagnosis on a patient's family. They can help allay unrealistic fears, reassure the patient about ongoing care, provide realistic hope about treatment or symptom relief, assess family function and caregiver burden, allow expression of concerns by the patient and family, and express empathy. When necessary, timely and appropriate referrals for mental health and social services can be made.

Kiernan GN, Frame PS. Cancer occurrence and screening in family practice. A 20-year experience. J Fam Pract. 1996;43:49-55.

Brotzman GL, Robertson RG. Role of the primary care physician after the diagnosis of cancer. Prim Care. 1998;25:401-6.

Earle CC, Neville BA. Under use of necessary care among cancer survivors. Cancer. 2004;101:1712-9.

Burge F, Lawson B, Johnston G. Family physician continuity of care and emergency department use in end-of-life cancer care. Med Care. 2003;41:992-1001.

Burge F, Lawson B, Johnston G, Cummings I. Primary care continuity and location of death for those with cancer. J Palliat Med. 2003;6:911-8.

Baile WF, Buckman R, Lenzi R, Glober G, Beale EA, Kudelka AP. SPIKES-A six-step protocol for delivering bad news. Oncologist. 2000;5:302-11.

Ptacek JT, Eberhardt TL. Breaking bad news. A review of the literature. JAMA. 1996;276:496-502.

Hagerty RG, Butow PN, Ellis PA, Lobb EA, Pendlebury S, Leighl N, et al. Cancer patient preferences for communication of prognosis in the metastatic setting. J Clin Oncol. 2004;22:1721-30.

Butow PN, Dowsett S, Hagerty R, Tattersall MH. Communicating prognosis to patients with metastatic disease: what do they really want to know?. Support Care Cancer. 2002;10:161-8.

Jenns K. Importance of nausea. Cancer Nurs. 1994;17:488-93.

Hesketh PJ, Kris MG, Grunberg SM, Beck T, Hainsworth JD, Harker G, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15:103-9.

Hesketh PJ, Gandara DR. Serotonin antagonists: a new class of anti-emetic agents. J Natl Cancer Inst. 1991;83:613-20.

Koeller JM, Aapro MS, Gralla RJ, Grunberg SM, Hesketh PJ, Kris MG, et al. Antiemetic guidelines. Support Care Cancer. 2002;10:519-22.

Grunberg SM, Koeller JM. Palonosetron: a unique 5-HT₃-receptor antagonist for the prevention of chemotherapy-induced emesis. Expert Opin Pharmacother. 2003;4:2297-303.

Andrews PL, Bhandari P, Davey PT, Bingham S, Marr HE, Blower PR. Are all 5-HT₃ receptor antagonists the same?. Eur J Cancer. 1992;28A(suppl 1):S2-6.

Eisenberg P, Figueroa-Vadillo J, Zamora R, Charu V, Hajdenberg J, Cartmell A, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT₃ receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-82.

Roila F, Tonato M, Cognetti F, Cortesi E, Favalli G, Marangolo M, et al. Prevention of cisplatin-induced emesis: a double-blind multicenter randomized crossover study comparing ondansetron and ondansetron plus dexamethasone. J Clin Oncol. 1991;9:675-8.

Hesketh PJ, Grunberg SM, Gralla RJ, Warr DG, Roila F, de Wit R, et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin. J Clin Oncol. 2003;21:4112-9.

de Wit R, Herrstedt J, Rapoport B, Carides AD, Guoguang-Ma J, Elmer M, et al. The oral NK(1) antagonist, aprepitant, given with standard anti-emetics provides protection against nausea and vomiting over multiple cycles of cisplatin-based chemotherapy. Eur J Cancer. 2004;40:403-10.

Harding RK, Young RW, Anno GH. Radiotherapy induced emesis. In: Andrews PL, Sanger GJ, eds. Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. New York, N.Y.: Chapman & Hall Medical, 1993: 163–78.

Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, et al. 2002 Guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002;34:730-51.

Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med. 1966;64:328-40.

Cometta A, Calandra T, Gaya H, Zinner SH, de Bock R, Del Favero A, et al. Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granu-locytopenic patients with cancer. Antimicrob Agents Chemother. 1996;40:1108-15.

National Comprehensive Cancer Network. Antiemesis. In: Clinical Practice Guidelines in Oncology. Accessed June 20, 2006, at: http://www.nccn.org/professionals/physician_gls/default.asp.

Rosenoff SH. Octreotide LAR resolves severe chemotherapy-induced diarrhoea (CID) and allows continuation of full-dose therapy. Eur J Cancer Care. 2004;13:380-3.

Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol. 2002;20:4083-107.

Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennet C, et al. Erythropoietin for patients with malignant disease. Cochrane Database Syst Rev. 2005;4:CD003407.

Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B for the Epoetin Alfa Study Group. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2001;19:2865-74.

Innocenti M, Moscatelli G, Lopez S. Efficacy of gelclair in reducing pain in palliative care patients with oral lesions: preliminary findings from an open pilot study. J Pain Symptom Manage. 2002;24:456-7.

Pazdur R. Cancer Management: A Multidisciplinary Approach: Medical, Surgical, & Radiation Oncology. 7th ed. New York, N.Y.: Oncology Group, 2003.

Crawford J, Cella D, Cleeland CS, Cremieux PY, Demetri GD, Sarokhan BJ, et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer. 2002;95:888-95.

Cervantes A, Chirivella I. Oncological emergencies. Ann Oncol. 2004;15(suppl 4):iv-306.

Walsh D, Donnelly S, Rybicki L. The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer. 2000;8:175-9.

Patrick DL, Ferketich SL, Frame PS, Harris JJ, Hendricks CB, Levin B, et al. National Institutes of Health state-of-the-science conference statement: symptom management in cancer: pain, depression, and fatigue, July 15–17, 2002. J Natl Cancer Inst. 2003;95:1110-7.

Hwang SS, Chang VT, Cogswell J, Kasimis BS. Clinical relevance of fatigue levels in cancer patients at a Veterans Administration Medical Center. Cancer. 2002;94:2481-9.

Chang VT, Hwang SS, Feuerman M, Kasimis BS. Symptom and quality of life survey of medical oncology patients at a Veterans Affairs medical center: a role for symptom assessment. Cancer. 2000;88:1175-83.

Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist. 2000;5:353-60.

National Comprehensive Cancer Network. Cancer-related fatigue. In: Clinical Practice Guidelines in Oncology. Accessed June 20, 2006, at: http://www.nccn.org/professionals/physician_gls/default.asp.

Stevinson C, Lawlor DA, Fox KR. Exercise interventions for cancer patients. Cancer Causes Control. 2004;15:1035-56.

Uitterhoeve RJ, Vernooy M, Litjens M, Potting K, Bensing J, De Mulder P, et al. Psychosocial interventions for patients with advanced cancer—a systematic review of the literature. Br J Cancer. 2004;91:1050-62.

Portenoy RK, Lesage P. Management of cancer pain. Lancet. 1999;353:1695-700.

van't Spijker A, Trijsburg RW, Duivenvoorden HJ. Psychological sequelae of cancer diagnosis. Psychosom Med. 1997;59:280-93.

Massie MJ. Prevalence of depression in patients with cancer. J Natl Cancer Inst Monogr. 2004(32):57-71.

Watson M, Haviland JS, Greer S, Davidson J, Bliss JM. Influence of psychological response on survival in breast cancer: a population-based cohort study. Lancet. 1999;354:1331-6.

Goodwin JS, Zhang DD, Ostir GV. Effect of depression on diagnosis, treatment, and survival of older women with breast cancer. J Am Geriatr Soc. 2004;52:106-11.

Greenberg DB. Barriers to the treatment of depression in cancer patients. J Natl Cancer Inst Monogr. 2004(32):127-35.

Passik SD, Dugan W, McDonald MV, Rosenfeld B, Theobald DE, Edgerton S. Oncologists' recognition of depression in their patients with cancer. J Clin Oncol. 1998;16:1594-600.

Fisch M. Treatment of depression in cancer. J Natl Cancer Inst Monogr. 2004(32):105-11.

Fisch MJ, Loehrer PJ, Kristeller J, Passik S, Jung SH, Shen J, et al. Fluoxetine versus placebo in advanced cancer outpatients: a double-blinded trial of the Hoosier Oncology Group. J Clin Oncol. 2003;21:1937-43.

National Comprehensive Cancer Network. Distress management. In: Clinical Practice Guidelines in Oncology. Accessed June 20, 2006, at: http://www.nccn.org/professionals/physician_gls/default.asp.

Brown JK, Byers T, Doyle C, Coumeya KS, Demark-Wahnefried W, Kushi LH, et al.; for the American Cancer Society. Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J Clin. 2003;53:268-91.

Tisdale MJ. Cancer anorexia and cachexia. Nutrition. 2001;17:438-42.

Berenstein EG, Ortiz Z. Megestrol acetate for the treatment of anorexia-cachexia syndrome. Cochrane Database Syst Rev. 2005;2:CD004310.

Von Roenn JH, Paice JA. Control of common, non-pain cancer symptoms. Semin Oncol. 2005;32:200-10.

Gordon JN, Trebble TM, Ellis RD, Duncan HD, Johns T, Goggin PM. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut. 2005;54:540-5.

Burns CP, Halabi S, Clamon G, Kaplan E, Hohl RJ, Atkins JN, et al. Phase II study of high-dose fish oil capsules for patients with cancer-related cachexia. Cancer. 2004;101:370-8.

Wigmore SJ, Barber MD, Ross JA, Tisdale MJ, Fearon KC. Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer. 2000;36:177-84.

Gogos CA, Ginopoulos P, Salsa B, Apostolidou E, Zoumbos NC, Kalfarentzos F. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy. Cancer. 1998;82:395-402.

Richardson MA, Sanders T, Palmer JL, Greisinger A, Singletary SE. Complementary/alternative medicine use in a comprehensive cancer center and the implications for oncology. J Clin Oncol. 2000;18:2505-14.

DiGianni LM, Garber JE, Winer EP. Complementary and alternative medicine use among women with breast cancer. J Clin Oncol. 2002;20(18 suppl):34S-8S.

Fellowes D, Barnes K, Wilkinson S. Aromatherapy and massage for symptom relief in patients with cancer. Cochrane Database Syst Rev. 2004;3:CD002287.

Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the United States: potential adverse interactions with anticancer agents. J Clin Oncol. 2004;22:2489-503.

Manne S. Cancer in the marital context: Cancer Invest. 1998;16:188-202.

Taylor-Brown J, Kilpatrick M, Maunsell E, Dorval M. Partner abandonment of women with breast cancer. Myth or reality?. Cancer Pract. 2000;8:160-4.

Dorval M, Guay S, Mondor M, Masse B, Falardeau M, Robidoux A, et al. Couples who get closer after breast cancer: frequency and predictors in a prospective investigation. J Clin Oncol. 2005;23:3588-96.

Visser A, Huizinga GA, van der Graaf WT, Hoekstra HJ, Hoekstra-Weebers JE. The impact of parental cancer on children and the family: a review of the literature. Cancer Treat Rev. 2004;30:683-94.

Grunfeld E, Coyle D, Whelan T, Clinch J, Reyno L, Earle CC, et al. Family caregiver burden. CMAJ. 2004;170:1795-801.